Glucuronidation
Encyclopedia
Glucuronidation is the addition of glucuronic acid
to a substrate. Glucuronidation is often involved in xenobiotic metabolism
of substances such as drug
s, pollutants, bilirubin
, androgen
s, estrogen
s, mineralocorticoid
s, glucocorticoid
s, fatty acid
derivatives, retinoid
s, and bile acid
s. These linkages involve glycosidic bond
s.
(Note: Glucuronic acid structure is incorrect as drawn.)
UDP-glucuronic acid (glucuronic acid linked via a glycosidic bond
to uridine diphosphate
) is an intermediate in the process and is formed in the liver
. One example is this N-glucuronidation of an aromatic amine
, 4-aminobiphenyl
, by UGT1A4 or UGT1A9 from human, rat, or mouse liver.
The substances resulting from glucuronidation are known as glucuronide
s (or glucuronosides) and are typically much more water
-soluble than the non-glucuronic acid-containing substance from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or faeces (via bile from the liver). Hormone
s may also be glucuronidated to allow for easier transport around the body. Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of substances. Sometimes toxic substances are also less toxic after glucuronidation.
The conjugation of xenobiotic molecules with hydrophilic molecular species such as glucuronic acid is known as phase II metabolism.
, although the enzyme responsible for its catalysis
, UDP-glucuronyltransferase, has been found in all major body organs, e.g., intestine
, kidney
s, brain
, adrenal gland
, spleen
, and thymus
.
. Generally, an increased rate of glucuronidation results in less effect of affected drugs or compounds, and vice versa.
Glucuronic acid
Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic acid...
to a substrate. Glucuronidation is often involved in xenobiotic metabolism
Xenobiotic metabolism
Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons...
of substances such as drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s, pollutants, bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
, androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s, estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s, mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
s, glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s, fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
derivatives, retinoid
Retinoid
The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth....
s, and bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
s. These linkages involve glycosidic bond
Glycosidic bond
In chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
s.
Mechanism
Glucuronidation consists of transfer of the glucuronic acid component of UDP-glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase.
(Note: Glucuronic acid structure is incorrect as drawn.)
UDP-glucuronic acid (glucuronic acid linked via a glycosidic bond
Glycosidic bond
In chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
to uridine diphosphate
Uridine diphosphate
Uridine diphosphate, abbreviated UDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside uridine. UDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase uracil.-See also:* Nucleoside...
) is an intermediate in the process and is formed in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. One example is this N-glucuronidation of an aromatic amine
Aromatic amine
An aromatic amine is an amine with an aromatic substituent - that is -NH2, -NH- or nitrogen group attached to an aromatic hydrocarbon, whose structure usually contains one or more benzene rings. Aniline is the simplest example....
, 4-aminobiphenyl
4-Aminobiphenyl
4-Aminobiphenyl is an amine derivative of biphenyl. It is used to manufacture azo dyes. It is a known human carcinogen and so it has been largely replaced by less toxic compounds. It is similar to benzidine....
, by UGT1A4 or UGT1A9 from human, rat, or mouse liver.
The substances resulting from glucuronidation are known as glucuronide
Glucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
s (or glucuronosides) and are typically much more water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
-soluble than the non-glucuronic acid-containing substance from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or faeces (via bile from the liver). Hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s may also be glucuronidated to allow for easier transport around the body. Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of substances. Sometimes toxic substances are also less toxic after glucuronidation.
The conjugation of xenobiotic molecules with hydrophilic molecular species such as glucuronic acid is known as phase II metabolism.
Sites
Glucuronidation occurs mainly in the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, although the enzyme responsible for its catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
, UDP-glucuronyltransferase, has been found in all major body organs, e.g., intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, and thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
.
General influencing factors
Various factors affect the rate of glucuronidation, in turn causing increased or decreased glucuronidation of various substances, in turn affecting their clearanceClearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
. Generally, an increased rate of glucuronidation results in less effect of affected drugs or compounds, and vice versa.
| Factor | Effect on glucuronidation | Main drugs or compounds affected | |
|---|---|---|---|
| Age | Infant | ↑ | Chloramphenicol Chloramphenicol Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is... , morphine Morphine Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more... , acetaminophen, bilirubin Bilirubin Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases... , steroids |
| Elderly | ↑ or unchanged | No change found for acetaminophen, oxazepam Oxazepam Oxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative... , temazepam Temazepam Temazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep... , or propranolol. Decreased clearance found for codeine Codeine Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties... -6-glucuronide, and decreased unbound clearance for oxazepam in the very elderly. |
|
| Gender | Females | ↓ | Clearance higher in males for acetaminophen, oxazepam, temazepam, and propranolol. Possible additive role with CYP1A2 resulting in higher clozapine and olanzapine concentrations in females |
| Males | ↑ | ||
| Body habitus | Overweight | ↑ | Clearance of lorazepam, oxazepam, temazepam, and acetaminophen likely the result of an increase in liver size and quantity of enzyme |
| Underweight/malnourished | ↓ | Chloramphenicol, acetaminophen | |
| Disease states | Fulminant hepatitis, cirrhosis | ↓ | Zidovudine, oxazepam, lamotrigine |
| Hypothyroidism | ↓ | Oxazepam, acetaminophen | |
| HIV | ↓ | Acetaminophen | |
| Tobacco smoking Tobacco smoking Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes... |
↑ | Propranolol, oxazepam, lorazepam, acetaminophen. Possible additive role with CYP1A2 induction causing decreased clozapine and olanzapine concentration. |
|
Affected drugs
Many drugs which are substrates for glucuronidation as part of their metabolism are significantly affected by inhibitors or inducers of their specific glucuronisyltransferase types:| Substrate | Inhibitors of glucuronidation | Inducers of glucuronidation |
|---|---|---|
| Morphine |
|
|
| Oxazepam |
|
|
| Bilirubin |
|
|
| Acetaminophen |
|
|
| Androsterone |
|
|
| Carbamazepine- 10,1 1-transdiol |
|
|
| Codeine |
|
|
| Lamotrigine |
|
|
| Lorazepam |
|
|
| Temazepam |
|
|
| Testosterone |
|
|
| Zidovudine |
|